Heart failure (HF) patients show brain injury in regions which control the autonomic (insular lobes), cognition (hippocampus, frontal cortex), and breathing (cerebellum) functions. Abnormalities in these sites are associated with symptoms which are linked to increased morbidity and mortality and decreased quality of life in HF. However, the underlying cause of brain injury in these areas in HF is unclear. Alteration in blood- brain barrier (BBB) function is a potential cause of brain damage in HF, as functional changes in the BBB are associated with neural injury in other diseases. However, there are no published reports of BBB changes in HF or regarding any association between BBB function and brain damage in this condition. Using non-invasive brain magnetic resonance imaging (MRI) procedures, our preliminary studies are the first to report BBB abnormalities (via diffusion-weighted pseudo-continuous arterial spin labeling [pCASL] procedures) in HF and that these BBB changes are associated with brain injury (as examined by diffusion tensor imaging based mean diffusivity [MD], an MRI measure of tissue integrity) in the insular lobes, hippocampus, frontal cortices, and cerebellar regions in HF subjects compared to controls. However, while promising, the sample size in this preliminary study was quite small and did not allow us to control for important covariates, such as age and gender. Therefore, the specific aims of this proposal are to: 1) compare global BBB function (calculated from diffusion-weighted pCASL) between HF and age- and gender-matched control subjects; 2) compare regional brain injury (assessed by MD) in the insular lobes, hippocampus, frontal cortices, and cerebellum between HF and age- and gender-matched healthy controls; 3) examine the relationship between altered BBB function (as indicated by diffusion-weighted pCASL data) and insular, hippocampal, frontal, and cerebellar injury (as indicated by MD measures) in HF patients. In summary, HF patients show significant regional brain injury in areas that control autonomic, cognitive, and breathing functions. A potential cause of this brain injury may be alterations in the BBB function. Abnormal BBB activity has not been reported previously in HF, but our preliminary studies have shown that BBB function is compromised and that this alteration is associated with brain injury in areas which control autonomic, cognitive, and breathing functions. The proposed study will examine global BBB function, assess regional tissue injury, and evaluate the relationships between BBB function and brain injury. Information from this study has the potential to disclose the processes contributing to brain injury in HF. Thus, it has important implications on identification of effectve treatments for HF by repairing BBB function, as used in other conditions (such as stroke), which could dramatically improve the mortality, morbidity, and quality of life in this high risk patient population.